Shear stress, the frictional force due to blood flow, regulates arterial pressure, vascular remodeling, cardiac and vascular embryogenesis, atherogenesis and immune responses, including migration of leukocytes into tissue. The observation that atherosclerotic plaque forms preferentially at sites of disturbed blood flow suggests that flow patterns can regulate the chronic inflammation associated with atherogenesis. Despite the importance of mechanotransduction in vascular function and pathology, the molecular mechanisms by which endothelial cells sense and respond to fluid shear stress are not well understood. Our long term goal is to understand how shear stress-dependent inflammatory signaling can be modulated for preventive and therapeutic purposes. The objective of this application is to determine how endothelial cells sense and transduce shear stress. Based on our preliminary data, we hypothesize that PECAM-1 senses mechanical force while VE-cadherin plays an accessory signaling role in inflammatory and atherogenic signals in response to flow. In particular, we hypothesize that these junctional receptors regulate cytoskeletal rearrangements, transcriptional responses, adhesion molecule expression and leukocyte transmigration under flow. By expanding our understanding of PECAM-1- and VE-cadherin-mediated signaling, we are in an excellent position to refine the present understanding of how cells respond to shear stress. To do this, we propose three aims: Specific aim #1: Determine regions in PECAM-1 required to initiate signaling in response to shear stress; Specific aim #2: Determine the role of PECAM-1 and VE-cadherin in shear stress-dependent inflammatory responses; Specific aim #3: Determine the role of PECAM-1 in inflammatory and atherogenic signals in a mouse model of carotid flow-mediated remodeling. [unreadable] [unreadable] Altogether, this research will improve our understanding of how endothelial cells sense physiological fluid shear stress and thus "promote" atherogenesis and inflammation. In addition to the basic science, delineation of these pathways should be of value from an applied perspective: development of therapies that interrupt mechanochemical signaling pathways in endothelial cells will have the potential to alter the course of cardiovascular disease and inflammation. The proposed research will improve our understanding of why atherosclerosis plaques develop in specific regions in the vascular tree and may lead to development of therapies for cardiovascular disease and inflammation. [unreadable] [unreadable] [unreadable]